Apoptosis or programmed cell death is a key process for the normal development and function of multicellular organisms. Damaged or undesired cells in organisms are removed by both the intrinsic apoptotic pathway occurred in mitochondria and the extrinsic apoptotic pathway caused by binding of death ligands (e.g. Fas ligand) to the corresponding receptors (e.g. Fas receptor) (Cell, 2003, 112, 481-490 Science 1998, 281, 1305-1308 Cell, 1999, 96, 245-254). Physiological cell death plays important roles in a wide variety of normal processes, however, aberrant apoptosis causes diverse human diseases (Science 1995, 267, 1456-1462 Nat. Rev. Drug Dis. 2002, 1, 111-121 Nat. Rev. Mol. Cell. Biol. 2000, 1, 120-129). For example, retarded apoptosis contributes to diverse human tumours and the failure to eliminate autoreactive lymphocytes (autoimmunity). In contrast, excessive apoptosis results in neurodegenerative diseases and cardiovascular diseases. Since apoptosis is involved in a wide variety of aforementioned human diseases, research on apoptosis has become one of central areas in biomedical applications. Small molecules that either induce or prevent apoptotic cell death are significantly useful for understanding the mechanisms of action of apoptotic regulatory proteins. In addition, these small molecules can be used as novel therapeutic agents to treat apoptosis-related diseases, such as cancers and autoimmune diseases (Science 1995, 267, 1456-1462 Nat. Rev. Drug Dis. 2002, 1, 111-121 Nat. Rev. Mol. Cell. Biol. 2000, 1, 120-129 Chem. Biol. 2002, 9, 1059-1072 Nat. Chem. Biol. 2006, 2, 543-550).
Various proteins including Bcl-2 (B cell lymphoma-2) and IAP (inhibitor of apoptosis protein) families are involved in apoptotic pathways. Caspases with aspartate specificity are the main executioner enzymes in apoptotic cell death (Science 1998, 281, 1312-1316). Interestingly, chaperone heat shock cognate 70 (Hsc70) suppresses apoptotic cell death by directly associating with apoptosis-inducing factors such as Apaf-1 (EMBO J. 1997, 16, 6209-6216 Nat. Cell. Biol. 2001, 3, 839-843). Hsc70 plays various roles in cellular processes, such as protein folding of newly synthesized cytoplasmic proteins, refolding of damaged proteins, degradation of misfolded proteins and translocation of cytoplasmic proteins across organellar membranes (Nature 1996, 381, 571-579 Cell 1998, 92, 351-366 Science 1999, 286, 1888-1893). It is known that inhibitors for Hsc70, that induce apoptosis, can be used as anticancer drugs (Genes Dev. 2005, 19, 570-582 Proc. Natl. Acad. Sci. USA 2000, 97, 7871-7876) and immunosuppressants (Pediatr Transplant. 2004, 8, 594-599 J. Clin. Pharmacol. 1998, 38, 981-993). Therefore, small molecules that induce apoptotic cell death by inhibiting Hsc70 are useful for both basic biological research to understand the mechanisms of action of apoptotic regulatory proteins and development of novel therapeutic agents to treat apoptosis-related diseases such as cancers and immune-related diseases.